This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hepatitis C virus (HCV) establishes chronic infection in the liver of nearly 80% of those infected and in addition to causing hepatitis, may cause liver cirrhosis and hepatocellular carcinoma. These detrimental long-term sequelae of persistent HCV infection now comprise the leading indication for liver transplantation in the United States. Defining the elements of the immune response that fail or are insufficient to mediate HCV infection resolution in the majority of those infected is critical for advancing our understanding of how to therapeutically intervene in HCV disease pathogenesis and is the focus of our work. The interaction between CD4+ T cells and professional antigen presenting cells (APCs) is insufficient in HCV infected individuals, and that the resultant failure to generate and maintain a robust CD4+ T helper response contributes to viral persistence through alteration of the CD8+ T cell effector response. We have successfully characterized the phenotype of HCV specific T cells and have found that the cells express high levels of PD-1 and low levels of CD127, an exhausted phenotype correlating with poor effector function. These cells are also uniquely susceptible to apoptosis. Interestingly, we have also been able to identify a complete panel of HCV epitopes to which HCV specific T cells should respond (submitted) which will now allow for identification of specific immune deficits that may be targets for immune augmentation. Together, these studies will help unravel the interplay between the APC and the T cell and elucidate mechanistic failures in the antiviral response.